T cell receptor–induced phosphoinositide-3-kinase p110δ activity is required for T cell localization to antigenic tissue in mice
Sarah J. Jarmin, … , Klaus Okkenhaug, Federica M. Marelli-Berg
Sarah J. Jarmin, … , Klaus Okkenhaug, Federica M. Marelli-Berg
Published February 7, 2008
Citation Information: J Clin Invest. 2008;118(3):1154-1164. https://doi.org/10.1172/JCI33267.
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Research Article Immunology

T cell receptor–induced phosphoinositide-3-kinase p110δ activity is required for T cell localization to antigenic tissue in mice

Abstract

The establishment of T cell–mediated inflammation requires the migration of primed T lymphocytes from the blood stream and their retention in antigenic sites. While naive T lymphocyte recirculation in the lymph and blood is constitutively regulated and occurs in the absence of inflammation, the recruitment of primed T cells to nonlymphoid tissue and their retention at the site are enhanced by various inflammatory signals, including TCR engagement by antigen-displaying endothelium and resident antigen-presenting cells. In this study, we investigated whether signals downstream of TCR ligation mediated by the phosphoinositide-3-kinase (PI3K) subunit p110δ contributed to the regulation of these events. T lymphocytes from mice expressing catalytically inactive p110δ displayed normal constitutive trafficking and migratory responses to nonspecific stimuli. However, these cells lost susceptibility to TCR-induced migration and failed to localize efficiently to antigenic tissue. Importantly, we showed that antigen-induced T cell trafficking and subsequent inflammation was abrogated by selective pharmacological inhibition of PI3K p110δ activity. These observations suggest that pharmacological targeting of p110δ activity is a viable strategy for the therapy of T cell–mediated pathology.

Authors

Sarah J. Jarmin, Rachel David, Liang Ma, Jan-Guo Chai, Hamlata Dewchand, Aya Takesono, Anne J. Ridley, Klaus Okkenhaug, Federica M. Marelli-Berg

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Figure 4

PI3K p110δ activation by TCR but not CD28 is required for antigen-dependent T cell recruitment.

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PI3K p110δ activation by TCR but not CD28 is required for antigen-depend...
(A and B) H2-Ab–restricted HY-specific WT (black bars), CD28Y170F (white bars), and p110δD910A (light gray bars) CD4+ T cells were injected i.v. into male mice (107/mouse) that had received an i.p. injection of IFN-γ (600 U) 48 hours earlier. The following day, mice were sacrificed, and the presence of fluorescently labeled cells in the peritoneal cavity (A) and membrane (B) was assessed by flow cytometry and wide-field fluorescence microscopy, respectively. To facilitate visualization by flow cytometry, cells were double stained with an APC-conjugated anti-CD4 antibody following harvesting. The mean T cell numbers ± SEM observed in samples from at least 3 animals are shown. A: *P < 0.04, CD28Y170F versus WT T cells; **P < 0.001, p110δD910A versus WT T cells; P < 0.005, p110δD910A versus CD28Y170F T cells. B: *P < 0.03, CD28Y170F versus WT T cells; **P < 0.002, p110δD910A versus WT T cells; P < 0.007, p110δD910A versus CD28Y170F T cells. (C and D) HY-specific WT or p110δD910A CD4+ T cells that had either undergone antibody-mediated CD28 ligation (30 minutes at 37°C, PKH26-labeled) or had been pretreated with an antibody isotype control (IsC) (CFSE-labeled) were injected i.v. (107/mouse) into male mice that had received an i.p. injection of IFN-γ 48 hours earlier. The presence of fluorescently labeled cells in the peritoneal cavity (C) and membrane (D) was assessed 24 hours later as described for A and B. The mean T cell number ± SEM observed in samples from at least 3 animals is shown. C: *P < 0.02 versus WT + IsC; D: *P < 0.02 versus WT + IsC.